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Achaete-scute homolog 1 is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''ASCL1''
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. Because it was discovered subsequent to studies on its homolog in
Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...
, the
Achaete-scute complex The ''achaete-scute'' complex (''AS-C'') is a group of four genes (''achaete'', ''scute'', ''lethal of scute'', and ''asense'') in the fruit fly ''Drosophila melanogaster''. These genes encode basic helix-loop-helix transcription factors that ...
, it was originally named MASH-1 for mammalian achaete scute homolog-1.


Function

This
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
encodes a member of the
basic helix-loop-helix BASIC (Beginners' All-purpose Symbolic Instruction Code) is a family of general-purpose, high-level programming languages designed for ease of use. The original version was created by John G. Kemeny and Thomas E. Kurtz at Dartmouth College ...
(BHLH) family of transcription factors. The protein activates transcription by binding to the
E box An E-box (enhancer box) is a Response element, DNA response element found in some eukaryotes that acts as a protein-binding site and has been found to regulate gene expression in neurons, muscles, and other tissues. Its specific DNA sequence, CANNTG ...
(5'-CANNTG-3').
Dimerization A dimer () (''wikt:di-, di-'', "two" + ''-mer'', "parts") is an oligomer consisting of two monomers joined by bonds that can be either strong or weak, Covalent bond, covalent or Intermolecular force, intermolecular. Dimers also have significant im ...
with other BHLH proteins is required for efficient DNA binding. This protein plays a role in the neuronal commitment and differentiation and in the generation of olfactory and autonomic
neurons A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
. It is highly expressed in
medullary thyroid cancer Medullary thyroid cancer is a form of Thyroid cancer, thyroid carcinoma which originates from the parafollicular cells (C cells), which produce the hormone calcitonin.Hu MI, Vassilopoulou-Sellin R, Lustig R, Lamont JP"Thyroid and Parathyroid Cance ...
and
small cell lung cancer Small-cell carcinoma is a type of highly malignant cancer that most commonly arises within the lung, although it can occasionally arise in other body sites, such as the cervix, prostate, and gastrointestinal tract. Compared to non-small cell car ...
and may be a useful marker for these cancers. The presence of a CAG repeat in the gene suggests that it may also play a role in tumor formation.


Role in neuronal commitment

Development of the vertebrate nervous system begins when the
neural tube In the developing chordate (including vertebrates), the neural tube is the embryonic precursor to the central nervous system, which is made up of the brain and spinal cord. The neural groove gradually deepens as the neural fold become elevated, a ...
forms in the early
embryo An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...
. The neural tube eventually gives rise to the entire
nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes th ...
, but first
neuroblasts In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...
must differentiate from the
neuroepithelium Neuroepithelial cells, or neuroectodermal cells, form the wall of the closed neural tube in early embryonic development. The neuroepithelial cells span the thickness of the tube's wall, connecting with the pial surface and with the ventricular or l ...
of the tube. The neuroblasts are the cells that undergo
mitotic division In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is maintai ...
and produce
neurons A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
. Asc is central to the differentiation of the neuroblasts and the
lateral inhibition In neurobiology, lateral inhibition is the capacity of an excited neuron to reduce the activity of its neighbors. Lateral inhibition disables the spreading of action potentials from excited neurons to neighboring neurons in the lateral direction ...
mechanism which inherently creates a safety net in the event of damage or death in these incredibly important cells. Differentiation of the neuroblast begins when the cells of the neural tube express Asc and thus upregulate the expression of
Delta Delta commonly refers to: * Delta (letter) (Δ or δ), a letter of the Greek alphabet * River delta, at a river mouth * D ( NATO phonetic alphabet: "Delta") * Delta Air Lines, US * Delta variant of SARS-CoV-2 that causes COVID-19 Delta may also ...
, a protein essential to the lateral inhibition pathway of neuronal commitment. Delta can diffuse to neighboring cells and bind to the
Notch receptor __NOTOC__ __FORCETOC__ Notch proteins are a family of type-1 transmembrane proteins that form a core component of the Notch signaling pathway, which is highly conserved in metazoans. The Notch extracellular domain mediates interactions with DSL fa ...
, a large transmembrane protein which upon activation undergoes
proteolytic cleavage Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases, ...
to release the intracellular domain (Notch-ICD). The Notch-ICD is then free to travel to the nucleus and form a complex with Suppressor of
Hairless Hairless, also known as H, is a well-characterized Drosophila gene. Since Hairless is a dominant loss of function mutation, many mutations to Hairless are embryonic lethal, but there are several viable hairless mutants. This specific Drosophila ...
(SuH) and
Mastermind Mastermind, Master Mind or The Mastermind may refer to: Fictional characters * Mastermind (Jason Wyngarde), a fictional supervillain in Marvel Comics, a title also held by his daughters: ** Martinique Jason, the first daughter and successor of the ...
. This complex acts as
transcription regulator In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from al ...
of Asc and accomplishes two important tasks. First, it prevents the expression of factors required for differentiation of the cell into a neuroblast. Secondly, it inhibits the neighboring cell's production of Delta. Therefore, the future neuroblast will be the cell that has the greatest Asc activation in the vicinity and consequently the greatest Delta production that will inhibit the differentiation of neighboring cells. The select group of neuroblasts that then differentiate in the neural tube are thus replaceable because the neuroblast's ability to suppress differentiation of neighboring cells depends on its own ability to produce Asc. This process of neuroblast differentiation via Asc is common to all animals. Although this mechanism was initially studied in Drosophila, homologs to all proteins in the pathway have been found in vertebrates that have the same bHLH structure.


Autonomic nervous system development

In addition to its important role in neuroblast formation, Asc also functions to mediate
autonomic nervous system The autonomic nervous system (ANS), formerly referred to as the vegetative nervous system, is a division of the peripheral nervous system that supplies viscera, internal organs, smooth muscle and glands. The autonomic nervous system is a control ...
(ANS) formation. Asc was initially suspected to play a role in the ANS when ASCL1 was found expressed in cells surrounding the dorsal
aorta The aorta ( ) is the main and largest artery in the human body, originating from the left ventricle of the heart and extending down to the abdomen, where it splits into two smaller arteries (the common iliac arteries). The aorta distributes ...
, the
adrenal glands The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex which ...
and in the developing
sympathetic chain The sympathetic trunks (sympathetic chain, gangliated cord) are a paired bundle of nerve fibers that run from the base of the skull to the coccyx. They are a major component of the sympathetic nervous system. Structure The sympathetic trunk lies j ...
during a specific stage of development. Subsequent studies of mice genetically altered to be MASH-1 deficient revealed defective development of both sympathetic and parasympathetic
ganglia A ganglion is a group of neuron cell bodies in the peripheral nervous system. In the somatic nervous system this includes dorsal root ganglia and trigeminal ganglia among a few others. In the autonomic nervous system there are both sympatheti ...
, the two constituents of the ANS.


Interactions

ASCL1 has been shown to
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with Myocyte-specific enhancer factor 2A.


References


Further reading

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External links

* * {{Regulome , activates = , inhibits = Notch , activated_by = , inhibited_by = Transcription factors